Sustained release latanoprost implant

ABSTRACT

The present invention provides a sustained release, biodegradable intraocular latanoprost implant for reducing elevated intraocular pressure in an individual in need thereof. The implant can be configured as a film (e.g., a rolled film) or extruded filament, either of which can be inserted into the eye of the individual to provide for extended release of latanoprost for several days. Upon insertion into the eye, a rolled film may unroll to provide a film having a high surface area to volume ratio for drug diffusion.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.61/480,657, filed Apr. 29, 2011, and U.S. Provisional Application61/480,630, filed Apr. 29, 2011. The contents of each of theseprovisional applications are hereby incorporated by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to biodegradable intraocular implants thatprovide for the sustained release of latanoprost, and to methods ofmaking these implants, and to methods of using these implants to reduceelevated intraocular pressure in individuals in need thereof.

2. Summary of the Related Art

Latanoprost is a prostaglandin F_(2α) analogue which is indicated in thetreatment of open-angle glaucoma or ocular hypertension in patients whoare intolerant of other intraocular pressure (IOP)—lowering medicationsor insufficiently responsive (i.e., failed to achieve target IOP aftermultiple measurements over time) to another IOP-lowering medication.Latanoprost may be used alone or in combination with other antiglaucomaagents.

Latanoprost is an isopropyl ester prodrug of an analog of prostaglandinF_(2α). It is hydrolyzed by esterases in the cornea to latanoprost acid,which is biologically active. The elimination of latanoprost acid fromplasma is rapid (half-life 17 minutes) after either ophthalmic orintravenous administration. Latanoprost's pharmacology makes it acandidate for formulation as an IOP lowering sustained release polymerimplant. However, its physicochemical properties make it an extremelychallenging molecule to incorporate into a biodegradable implant. Thatis, Latanoprost (MW 432.58) is a colorless to slightly yellow oil thatis very soluble in acetonitrile and freely soluble in acetone, ethanol,ethyl acetate, isopropanol, methanol and octanol. It is practicallyinsoluble in water.

It is believed that a latanoprost sustained release implant would be aneffective treatment for long-term reduction of intraocular pressureassociated with glaucoma or other ocular diseases.

BRIEF SUMMARY OF THE INVENTION

The present invention provides a sustained release biodegradable polymerimplant containing latanoprost. In one embodiment, latanoprost isincorporated into a solid biodegradable implant, wherein said implantcomprises a mixture of a polylactide (PLA) and a lactide-glycolidecopolymer (PLGA). The implant is fabricated by combining latanoprost,PLA and PLGA polymers by melt extrusion or by dissolving the componentsin a solvent and removing the solvent to recover a solid composite, e.g.a polymeric film or fiber, which may be fabricated into a sustainedrelease polymer implant containing latanoprost. The composite, in theform of a thin film, can be cut to any shape and dimension. For example,a disc shaped implant that is about 100 μM to about 500 μM thick andabout 2 to about 6 mm in diameter may be formed from a thin filmcomprising latanoprost. In ophthalmic use, this thin implant may berolled-up and inserted into the subTenon's space through a smallopening. Once inserted, it may unfurl either partially or completely toits original disc shape providing a large surface for drug diffusionthrough the sclera.

Accordingly, one embodiment is an intraocular implant comprising orconsisting of latanoprost and a biodegradable polymer matrix. Thelatanoprost can be incorporated in the polymer matrix. In certainembodiments the latanoprost is homogenously distributed throughout thepolymer matrix.

The implant can be prepared in the form of a film (e.g, a thin polymericfilm) or an extruded filament (i.e, fiber). The film can be prepared bya solvent casting method, and the extruded filament by a hot-meltextrusion method or by direct compression, as described herein.

The biodegradable polymer matrix in the film or extruded filament (i.e.,fiber) can comprise or consist of a poly(D-lactide), a poly(L-lactide),a poly(D,L-lactide), a polyglycolide, a poly(D,L-lactide-co-glycolide)(PLGA), or a combination thereof.

The percent of D,L-lactide in the PLGA can be about 0 to less than about100%, about 15-85%, or about 35-65%. In specific embodiments the molarratio of D,L-lactide to glycolide in the PLGA copolymer is about 75:25or about 50:50.

In certain embodiments, the film is about to about 100 μm to about 500μm thick and may be about 2 to about 6 mm in diameter. In a particularembodiment the intraocular implant is configured as a rolled film.

The film can be made by a solvent casting method and may contain about30% (w/w) latanoprost, 20-60% (w/w) of a poly(D,L-lactide), and about10-50% (w/w) of a poly(D,L-lactide-co-glycolide).

The filament (or fiber) can be made by a hot-melt extrusion method andmay comprise about 20-30% (w/w) latanoprost, about 40-80% (w/w) of apoly(D,L-lactide-co-glycolide), and about 0-20% of a poly(D,L-lactide).

In another embodiment, the filament comprises about 20-30% w/wlatanoprost, 40-60% (w/w) of a poly(D,L-lactide-co-glycolide), 0-20% ofa poly(D,L-lactide), and 0-10% w/w PEG 3350.

In another embodiment, the fiber comprises a mixture ofpoly(D,L-lactide) (PLA) and poly(D,L-lactide-co-glycolide) (PLGA)polymers. In a more specific embodiment, the fiber comprises from about20 to about 60 percent w/w PLA and from about 10 to about 50 percent whyPLGA.

In one embodiment, the film comprises a poly(D,L-lactide) (PLA) selectedfrom the group consisting of RESOMER® R208 and RESOMER® R203S, and apoly(D,L-lactide-co-glycolide) (PLGA) selected from the group consistingof RESOMER® RG752S and RESOMER® RG755S.

In one embodiment, the extruded fiber comprises poly(D,L-lactide) (PLA)RESOMER® R202S, and poly(D,L-lactide-co-glycolide) (PLGA) RESOMER®RG752S.

RESOMER® R202H is an acid terminated poly(D,L-lactide) having aninherent viscosity of about 0.16-0.24 dl/g, as measured for a 0.1%solution in chloroform at 25° C.

RESOMER® R208 is an ester terminated poly(D,L-lactide) having aninherent viscosity of about 1.8-2.2 dl/g, as measured for a 0.1%solution in chloroform at 25° C.

RESOMER® R202S is an ester terminated poly(D,L-lactide) having aninherent viscosity of about 0.16-0.24 dl/g, as measured for a 0.1%solution in chloroform at 25° C.

RESOMER® R203S is an ester terminated poly(D,L-lactide) having aninherent viscosity of about 0.25-0.35 dl/g, as measured for a 0.1%solution in chloroform at 25° C.

RESOMER® RG752S is an ester terminated poly(D,L-lactide-co-glycolide)having an inherent viscosity of about 0.16-0.24 dl/g (as measured for a0.1% solution in chloroform at 25° C.), and a D,L-lactide:glycolideratio of about 75:25.

RESOMER® RG755S is an ester terminated poly(D,L-lactide-co-glycolide)having an inherent viscosity of about 0.50-0.70 dl/g (as measured for a0.1% solution in chloroform at 25° C.), and a D,L-lactide:glycolideratio of about 75:25.

In one embodiment, the film comprises or consists of 30% w/wlatanoprost, 35% w/w R208, and 35% w/w RG755S.

In another embodiment, the film comprises or consists of 30%w/w/latanoprost, 35% w/w R208, and 35% w/w RG752S.

In another embodiment, the film comprises or consists of 30% w/wlatanoprost, 35% w/w R208, and 35% w/w R203S 35%.

In another embodiment, the film comprises or consists of 30% w/wlatanoprost, 35% w/w R203S, and 35% w/w RG755S.

In another embodiment, the film comprises or consists of 30% w/wlatanoprost, 20% w/w R208, and 50% w/w RG752S.

In another embodiment, the film comprises or consists of 30% w/wlatanoprost, 35% w/w R208, and 35% w/w RG752S.

In another embodiment, the film comprises or consists of 30% w/wlatanoprost, 50% w/w R208, and 20% w/w RG752S.

In another embodiment, the film comprises or consists of 30%latanoprost, 60% w/w R208, and 10% w/w RG752S.

In another embodiment, the intraocular implant is in the form of anextruded fiber comprising latanoprost incorporated in a biodegradablepolymer matrix.

The extruded intraocular implant (i.e., fiber) may further comprise apolyethylene glycol (PEG). The PEG can act as a plasticizing agent,making it possible to extrude the implant (i.e, to form the fiber) attemperatures lower than might otherwise be possible in the absence ofthe PEG. Lower extrusion temperatures are desirable to preservelatanoprost activity.

In one embodiment the PEG plasticizer is PEG 3350.

One embodiment provides for a biodegradable intraocular implant forreducing intraocular pressure in an eye of an individual in needthereof, the implant comprising latanoprost and a biodegradable polymer,wherein:

-   -   a) the implant does not contain bimatoprost;    -   b) the implant is in the form of a film or an extruded filament;    -   c) said filament optionally further comprises a polyethylene        glycol (PEG);    -   d) said film is about 100 μm to about 500 μm thick and about 2        to about 6 mm in diameter;    -   e) said biodegradable polymer is        -   i) an ester terminated poly(D,L-lactide) having an inherent            viscosity of about 1.8-2.2 dl/g (R208);        -   ii) an ester terminated poly(D,L-lactide) having an inherent            viscosity of about 0.16-0.24 dl/g (R202S);        -   iii) an acid terminated poly(D,L-lactide) having an inherent            viscosity of about 0.16-0.24 dl/g (R202H);        -   iv) an ester terminated poly(D,L-lactide) having an inherent            viscosity of about 0.25-0.35 dl/g (R203S);        -   v) an ester terminated poly(D,L-lactide-co-glycolide) having            an inherent viscosity of about 0.16-0.24 dl/g and a            D,L-lactide to glycolide ratio of about 75:25 (RG752S); or        -   vi) an ester terminated poly(D,L-lactide-co-glycolide)            having an inherent viscosity of about 0.50-0.70 dl/g and a            D,L-lactide to glycolide ratio of about 75:25 (RG755S); or        -   vii) a combination of any two or more of i, ii, iii, iv, v,            or vi;    -   f) wherein the solubility parameters for each of the        latanoprost, the biodegradable polymer(s), and the PEG differ        one from the other by no more than 10 MPa^(1/2); and wherein    -   g) the implant releases latanoprost continuously for at least 30        days after placement in the eye of the individual.

In another embodiment, the implant does not contain a prostamide.

The film can be in the form of a rolled film that can partially orcompletely unfurl upon insertion into the eye.

The filament can comprise about 5 to about 10% by weight PEG 3350.

In one embodiment the extruded latanoprost-containing filament does notcontain polyethylene glycol.

In one embodiment the film comprises or consists of about 30% by weightlatanoprost, about 35% by weight of an ester terminatedpoly(D,L-lactide) having an inherent viscosity of about 1.8-2.2 dl/g(R208), and about 35% by weight of an ester terminatedpoly(D,L-lactide-co-glycolide) having an inherent viscosity of about0.50-0.70 dl/g and a D,L-lactide:glycolide ratio of about 75:25(RG755S).

In one embodiment the film comprises or consists of about 30% by weightlatanoprost, about 35% by weight of an ester terminatedpoly(D,L-lactide) having an inherent viscosity of about 1.8-2.2 dl/g(R208), and about 35% by weight of an ester terminated poly(D,L-lactide)having an inherent viscosity of about 0.25-0.35 dl/g (R203S).

In one embodiment the extruded filament comprises or consists of about20% by weight latanoprost, about 75% by weight of an ester terminatedpoly(D,L-lactide-co-glycolide) having an inherent viscosity of about0.16-0.24 dl/g and a D,L-lactide:glycolide ratio of about 75:25(RG752S); and about 5% by weight of PEG 3350.

In one embodiment the extruded filament comprises or consists of about30% by weight latanoprost, about 40% by weight of an ester terminatedpoly(D,L-lactide-co-glycolide) having an inherent viscosity of about0.16-0.24 dl/g and a D,L-lactide:glycolide ratio of about 75:25(RG752S), about 20% by weight of an ester terminated poly(D,L-lactide)having an inherent viscosity of about 0.16-0.24 dl/g (R202S), and about10% by weight of PEG 3350.

In one embodiment the extruded filament comprises or consists of about20% by weight latanoprost, about 40% by weight of an ester terminatedpoly(D,L-lactide-co-glycolide) having an inherent viscosity of about0.16-0.24 dl/g and a D,L-lactide:glycolide ratio of about 75:25(RG752S); and about 40% by weight of an ester terminatedpoly(D,L-lactide) having an inherent viscosity of about 0.16-0.24 dl/g(R202S).

In one embodiment the extruded filament comprises or consists of about20% by weight latanoprost, about 40% by weight of an ester terminatedpoly(D,L-lactide) having an inherent viscosity of about 0.16-0.24 dl/g(RG202S), and about 40% by weight of an acid terminatedpoly(D,L-lactide) having an inherent viscosity of about 0.16-0.24 dl/g(R202H).

Another embodiment is a method of providing an ocular implant to aperson in need thereof, the method comprising rolling a film comprisinglatanoprost and a biodegradable polymer or combination of polymers intoa cylindrical shape, inserting said rolled film into the eye of apatient and allowing said film to unroll or partially unroll to providea large surface for drug diffusion. In certain embodiments the unrolledfilm is about 25 μM to about 500 μM thick, or about 100 μm to about 500μm thick and about 2 mm to about 6 mm in diameter. The person in needcan be a person suffering from elevated intraocular pressure, such as apatient that has glaucoma.

In certain embodiments the rolled film is inserted into the subTenon'sspace through a small opening and allowed to partially unfurl or unfurlto its original shape thereby providing a large surface for drugdiffusion through the sclera.

Another embodiment provides for a method of reducing intraocularpressure (i.e., treating ocular hypertension) in a subject in need, themethod comprising placing an ocular implant into an eye of the subject,the implant comprising latanoprost and a biodegradable polymer. Theocular implant can be a film (e.g., a rolled film) or an extrudedfilament as described herein. The implant can be placed into thevitreous body, subconjunctival space, subTenon's space, or anteriorchamber of the eye, for example.

Another embodiment is a method of fabricating an intraocular implantcomprising a thin film of latanoprost in a biodegradable polymer matrixby solvent casting, the method comprising dissolving one or morebiodegradable polymers and latanoprost in an appropriate organicsolvent, casting said solution onto a suitable substrate and removingsaid solvent to recover a thin film of latanoprost in a biodegradablepolymer matrix. In certain embodiments the solvent is selected from thegroup consisting of dichloromethane, ethanol, octanol, chloroform,acetone and acetonitrile. In certain embodiments the solution comprisesfrom 10 to 75% solids, wherein said solids comprise latanoprost, polymerand other components which are useful for modifying the release oflatanoprost from the resulting film and/or plasticizers of said polymerwhich contribute to the flexibility of the film.

One embodiment provides for a method of making a biodegradableintraocular implant comprising:

-   -   a) dissolving the biodegradable polymer(s) in an organic solvent        under constant stirring to form a first solution;    -   b) adding latanoprost to the first solution under constant        stirring to form a second solution;    -   c) sonicating the second solution to remove air bubbles;    -   d) casting the second solution into a glass dish;    -   e) evaporating the solvent to form a dry film; and    -   f) cutting the film into circular portions of about 2 to about 6        mm in diameter each.

Useful solvents include dichloromethane.

The method can further comprise rolling the circular portions to form arolled film implant that can partially or completely unfurl uponplacement in the eye of an individual suffering from elevatedintraocular pressure.

Another embodiment provides for a method of making a biodegradableintraocular implant, the method comprising: mixing PEG 3350, thelatanoprost, and the biodegradable polymer(s), to form a mixture; andextruding the mixture at a temperature of less than about 80° C. to forma filament that will release latanoprost continuously for at least 30days after placement in the eye of the individual.

Definitions

“About” means that the number, range, value or parameter so qualifiedencompasses ten percent more and ten percent less of the number, range,value or parameter.

A “patient in need” can be a human or non-human mammal suffering from anocular condition. The ocular condition may be a condition treatable witha latanoprost-containing implant. Examples of an ocular conditionstreatable with a latanoprost-containing implant include glaucoma andelevated intraocular pressure (or ocular hypertension).

“Treat”, “treating”, or “treatment” means a reduction or resolution orprevention of an ocular condition. A treatment is usually effective toreduce at least one symptom of an ocular condition.

“Therapeutically effective amount” means the level or amount of agentneeded to treat an ocular condition, or reduce a symptom associated withthe condition without causing significant negative or adverse sideeffects to the eye or a region of the eye. In view of the above, atherapeutically effective amount of latanoprost is an amount that iseffective in reducing intraocular pressure in an eye of an individual.

“Therapeutic component” means that portion of an implant other than thepolymer matrix comprising one therapeutic agent used to treat an ocularcondition. The therapeutic component can be a discrete region of animplant, or it may be homogenously distributed throughout the implant.

“Biodegradable polymer” means a polymer or polymers which degrade invivo, and wherein erosion of the polymer or polymers over time occursconcurrent with or subsequent to release of the therapeutic agent, e.g,the latanoprost. The terms “biodegradable” and “bioerodible” areequivalent and are used interchangeably herein. A biodegradable polymermay be a homopolymer, a copolymer, or a polymer comprising more than twodifferent polymeric units. The polymer can be a gel or hydrogel typepolymer. Examples include PLA or PLGA polymers or mixtures orderivatives thereof.

Prostamides (prostaglandin-ethanolamides) have been described by, forexample, Woodward et al. (2007) British Journal of Pharmacology150:342-352. Prostamides have been disclosed in, for example, U.S. Pat.Nos. 6,395,787 and 6,403,649.

The solubility parameter for a substance is a numerical value whichindicates the relative solvency behavior of that substance. The conceptis discussed and defined in US 2008/0145403.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-C show release profiles for latanoprost-containing formulationsof Example 1.

FIGS. 2A-C show release profiles for latanoprost-containing formulationsof Example 2.

DETAILED DESCRIPTION OF THE INVENTION

Latanoprost is very difficult to incorporate into biodegradable polymermatrices, because it is an oil. It has now been discovered, that thisproblem can be overcome by using a combination of high molecular weightPLA and PLGA polymers and fabricating the implant by melt extrusion orcasting in an appropriate solvent. The oily drug substance (DS), i.e.latanoprost, helps plasticize the polymer and allows the production of ahomogeneous polymer film. The appropriate combination of solvent andpolymer is based on the solubility parameters of the solvent andpolymers, e.g. the solubility parameter of dichloromethane is 19.8MPa^(0.5). It has been determined that dichloromethane is a good solventfor PLA and PLGA, which have solubility parameters of about 21.1MPa^(0.5) and about 22.1 MPa^(0.5), respectively. Thus, a solvent havinga solubility parameter of from 17.1 to 26.1 MPa^(0.5), preferably from17.6 to 25.6, e.g. 21.1 or 22.1 MPa^(0.5) may be used in the practice ofthis invention. Such solvents may include dichloromethane, isopropanol,ethanol, acetonitrile and octanol.

For purposes of forming a film or an extruded filament that will providefor a long-lasting extended and perhaps nearly linear rate oflatanoprost release, the solubility parameters of the latanoprost,biodegradable polymer(s), co-solvent (e.g., PEG 3350), and organicsolvent preferably differ by no more than about 10 MPa^(0.5) from oneanother. In one embodiment, the solubility parameters of the componentschosen for inclusion in the extruded implant or film differ by no morethan about 7 MPa^(0.5), one from the other.

The solubility parameter of PEG 3350 is about 20 MPa^(0.5).

When preparing an extruded filament with latanoprost, it is important tokeep the extrusion temperature as low as possible to avoid loss anddegradation of the latanoprost. The temperatures ordinarily needed toextrude drug-containing biodegradable polymer implants can cause thelatanoprost to degrade and/or bubble out of the mixture, thereby causingundesirable loss of the oily drug. This can be overcome by using aselect combination of low molecular weight polymers and a plasticizersuch as a polyethylene glycol (PEG) that are compatible with the drugsubstance. The oily DS (e.g. latanoprost) and PEG plasticize thepolymers to a degree that allows the mixture to be extruded at atemperature where the DS is not degraded or lost. In some embodiments,the latanoprost-containing polymer mixture is extruded at a temperatureof about 50° C., from about 50° C. to about 55° C., less than about 60°C., less than about 70° C., less than about 80° C., or at a temperaturefrom about 50° C. to less than about 80° C.

An extruded filament may be cut to implant lengths of from about 5 μm toabout 10 mm, e.g. about 1, 2, or 3 mm, or from about 10 μm to about 1mm. The implants may have any appropriate length so long as the diameterof the implant permits the implant to move through a needle. Thefilament can have a diameter of less than about 500 μm, or from about500 μm to about 1.5 mm.

The total weight of an implant can be less than about 250 μg or fromabout 250-5000 μg or more. For example, an extruded implant may weighabout 500 μg, about 1000 μg, or about 2000 μg.

Latanoprost (CAS Registry No. 130209-82-4) is disclosed in U.S. Pat.Nos. 6,429,226; 6,417,230; 6,187,813; 6,030,999; 5,849,791; 5,627,208;5,578,618; 5,422,368 and 5,296,504 and has the following structure:

In the present invention, latanoprost is incorporated into abiodegradable polymer composite by melt extrusion, direct compression,or by dissolving latanoprost in a solvent for latanoprost and thepolymer to form a solution of latanoprost and the polymer and removingsaid solvent to provide a solid composite of latanoprost and saidbiodegradable polymer. Said solid composite is preferably formed bycasting a film of said solution of latanoprost and the polymer andremoving said solvent to recover a thin film. The solubility parameterfor latanoprost is about 22 to about 24 MPa^(0.5).

The thickness of said film is controlled by adjusting the thickness ofsaid cast solution and/or the solids content of the latanoprost/polymersolution. Preferably said thickness is from about 25 to about 500 μM,e.g. from about 25 to about 75 μM.

Suitable polymeric materials or compositions for use in the implantinclude those materials, which are compatible, i.e. biocompatible, withthe eye so as to cause no substantial interference with the functioningor physiology of the eye. Such materials preferably are at leastpartially and more preferably substantially completely biodegradable orbioerodible or bioabsorbable.

Of interest for use in the implants of this invention are polymers ofhydroxyaliphatic carboxylic acids, either homopolymers or copolymers.Polyesters of interest include polymers of D-lactic acid, L-lactic acid,racemic lactic acid and glycolic acid, and combinations thereof.Generally, by employing the L-lactate or D-lactate, a slowly erodingpolymer or polymeric material is achieved, while erosion issubstantially enhanced with the lactate racemate.

Some preferred characteristics of the polymers or polymeric materialsfor use in the present invention may include biocompatibility,compatibility, ease of use of the polymer in making the implant of thepresent invention, a half-life in the physiological environment of atleast about 6 hours, preferably greater than about one day, and notsignificantly increasing the viscosity of the vitreous.

The biodegradable polymeric materials, which are included to form theimplant, are desirably subject to enzymatic or hydrolytic instability.Water-soluble polymers may be cross-linked with hydrolytic orbiodegradable unstable cross-links to provide useful water insolublepolymers. The degree of stability can be varied widely, depending uponthe choice of monomer, whether a homopolymer or copolymer is employed,employing mixtures of polymers, and whether the polymer includesterminal acid groups.

Equally important to controlling the biodegradation of the polymer isthe relative average molecular weight of the polymeric compositionemployed in the implant. Different molecular weights of the same ordifferent polymeric compositions may be included in the implant tomodulate the release profile. In certain implants, the relative averagemolecular weight of the polymer will range from about 9 to about 200 kD,usually from about 10 to about 54 kD, and more usually from about 12 toabout 45 kD.

In some implants, copolymers of glycolic acid and lactic acid are used,where the rate of biodegradation is controlled by the ratio of glycolicacid to lactic acid. The most rapidly degraded copolymer has roughlyequal amounts of glycolic acid and lactic acid. Homopolymers, orcopolymers having ratios other than equal, are more resistant todegradation. The ratio of glycolic acid to lactic acid will also affectthe brittleness of the implant, where a more flexible implant isdesirable for larger geometries. The percent of polylactic acid in thepolylactic acid polyglycolic acid (PLGA) copolymer can be 0-100%,preferably about 15-85%, more preferably about 35-65%. In some implants,a 50/50 PLGA copolymer is used.

The biodegradable polymer matrix of the intraocular implant comprises amixture of two or more biodegradable polymers, selected from the groupconsisting of PLA, PLGA and mixtures thereof. For example, the implantmay comprise a mixture of a first biodegradable polymer and a differentsecond biodegradable polymer, wherein at least one or more of thebiodegradable polymers may have terminal acid groups.

PLA/PLGA polymers from the RESOMER ® product line are available fromEvonik Industries AG, Germany, and include the following: ResomerMonomer ratio i.v. dL/g RG502 50:50 poly (D,L-lactide-co-glycolide) 0.2RG502H 50:50 poly (D,L-lactide-co-glycolide), acid end 0.2 RG503 50:50poly (D,L-lactide-co-glycolide) 0.3 RG504 50:50 poly(D,L-lactide-co-glycolide) 0.5 RG505 50:50 poly(D,L-lactide-co-glycolide) 0.7 RG506 50:50 poly(D,L-lactide-co-glycolide) 0.8 RG752 75:25 poly (D,Llactide-co-glycolide) 0.2 RG755 75:25 poly(D,L lactide-co-glycolide) 0.6RG756 75:25 poly(D,L lactide-co-glycolide) 0.8 RG858 85:15 poly(D,L-lactide-co-glycolide) 1.4 R202H poly (D,L-lactide), acid end 0.2R203 poly (D,L-lactide) 0.3 R206 poly (D,L-lactide) 0.6 R104 poly(D,L-lactide) (3500)

An intraocular implant comprising a thin film of latanoprost in abiodegradable polymer matrix may be made by solvent casting utilizingthe following method: The polymers are dissolved in an appropriatesolvent, like dichloromethane, with constant stirring. Latanoprost isadded and stirring maintained. The solution is sonicated for 5 min toremove any air bubbles, and this solution is then cast onto a suitablesubstrate (e.g. glass culture dish), covered with weigh paper to ensurecontrolled evaporation of solvent, and placed in a fume cupboardovernight. After evaporation of the solvent, the solid polymeric filmcontaining drug substance, i.e. latanoprost, is removed and stored in adesiccator prior to use.

The solvent is selected for its ability to dissolve sufficient polymerand latanoprost to provide solutions, which may be cast and evaporatedto form a thin flexible film of latanoprost surrounded by a matrix ofsaid polymer.

The solvent may be dichloromethane, chloroform, acetone, acetonitrile,etc. For solvating properties and ease of solvent removal acetone ordichloromethane, e.g. dichloromethane, is preferred.

The solution may comprise from 10 to 75% solids, e.g. 30 to 50%, whereinsaid solids comprise latanoprost, polymer and other components which areuseful for modifying the release of latanoprost from the resulting filmand/or plasticizers of said polymer which contribute to the flexibilityof the film.

The film-shaped implant made by solvent casting contains 30%Latanoprost, 0-70% of a biodegradable poly(D,L-lactide-co-glycolide)polymer (Resomer® RG755S or Resomer® RG752S) and 0-70% of abiodegradable poly(D,L-lactide) polymer (Resomer® 8208 or Resomer®R203S). The successful invention formulations are summarized in Table 1.As shown in Table 1, said preferred thin film implants comprise 30%latanoprost, 10-50% of a biodegradable poly(D,L-lactide-co-glycolide)polymer (Resomer® RG755S or Resomer® RG752s) and 20-60% of abiodegradable poly(D,L-lactide) polymer (Resomer® R208 and/or Resomer®R203S).

Examples of the most preferred thin film implant formulation of theinvention are latanoprost 30%, R208 35% and RG752S 35%; latanoprost 30%,R208 35% and RG755S 35%; latanoprost 30%, R208 35% and R203S 35%; andlatanoprost 30%, R203S 35% and R755S 35%.

Release of the drug (latanoprost) from an erodible polymer is theconsequence of several mechanisms or combinations of mechanisms. Some ofthese mechanisms include desorption from the implant's surface,dissolution, diffusion through porous channels of the hydrated polymerand erosion. Erosion can be bulk or surface or a combination of both.The shell of the intraocular implant may release drug at a rateeffective to sustain release of an amount of drug for more than one weekafter implantation into an eye. In certain implants, therapeutic amountsof drug are released for no more than about 30-35 days afterimplantation. For example, an implant may release the drug at a rateeffective to sustain a therapeutically effective amount of drug forabout one month (i.e., about 30 days) after being placed in an eye. Asanother example, the implant may release drug at a rate effective tosustain a therapeutically effective amount of drug for more than fortydays, such as for about six months.

The following examples are intended to illustrate the present invention.

EXAMPLE 1

TABLE 1 Latanoprost Containing Film Formulations w/w, % Resomer ResomerResomer Resomer Formulation No Latanoprost R208 R203S RG752S RG755SR-2007-8933-166 30 35 0 0 35 R-2007-8933-167 30 35 0 35 0R-2007-8933-168 30 35 35 0 0 R-2007-8933-169 30 0 35 0 35R-2009-9606-014 30 20 0 50 0 R-2009-9606-015 30 35 0 35 0R-2009-9606-016 30 50 0 20 0 R-2009-9606-017 30 60 0 10 0

Release studies were performed in triplicates as follows. The dried filmwas cut using 4-mm biopsy punch (approximately 2.0-mg), and was placedinto a 10-mL vial containing 0.01M phosphate buffered saline (pH7.4)+0.1% Triton X100. The samples were then transferred into a shakingwater bath set at 37° C. and 50 rpm. At various time-points, thesolution was removed and analyzed by HPLC for the amount of releasedlatanoprost. The removed solution is replaced with fresh phosphatebuffered saline solution. Drug release profiles are shown in FIGS. 1A-C.

The film-shaped implants made by solvent casting can be cut to any shapeand dimension. One example is a disc shaped implant 100 μm to 500 μmthick and 2 to 6 mm in diameter.

EXAMPLE 2

This example prepares an extruded solid polymer implant containinglatanoprost. While the above discussion relates mainly to the problemsof incorporating latanoprost in a film oily drug substances (DS) arealso very difficult to incorporate into hot-melt extruded implantsbecause they exude the oily DS when heated. It is important to keep theextrusion temperature as low as possible to avoid loss and degradationof the DS. This can be overcome by using a select combination ofpolymers and a plasticizer like PEG that are compatible with the drugsubstance. The oily DS and PEG plasticize the polymers to a degree thatallows the mixture to be extruded at a temperature where the DS is notdegraded or lost. Suitable formulations are shown in Table 2.

The polymer implants were made by hot-melt extrusion using amechanically driven ram microextruder, but they can also be made bydirect compression or solvent casting. The implants are rod-shaped, butthey can be made into any geometric shape by changing the extrusion orcompression die.

The samples were initially mixed using a spatula in a weigh-boat for 15minutes. The samples were then transferred into a stainless steelcontainer containing two ¼” stainless steel balls and mixing continuedusing a Turbula mixer for two separate 15-min cycles. The powder blendwas mixed by hand using a spatula between each cycle and after the finalcycle. The blended material was then compacted into an extruder barrelusing a pellet compactor; then the extruder barrel was placed into theheated well of the piston extruder and extruded using a 500 μm nozzle.

The implants made by hot-melt extrusion contain 20-30% Latanoprost,40-60% of a biodegradable poly(D,L-lactide-co-glycolide) polymer(Resomer® RG752s), 0-40% of a biodegradable poly(D,L-lactide) polymer(Resomer® R202s), 0-40% of a biodegradable poly(D,L-lactide) acid endcaped polymer (Resomer® R20214), and 0-10% PEG-3350. The successfulhot-melt extruded invention formulations are summarized in Table 2.

TABLE 2 Latanoprost Containing Extruded Filament Formulations w/w, %Resomer Resomer Resomer Formulation No Latanoprost RG752S R202S 202HPEG-3350 R-2008-8933-070 30 60 0 0 10 R-2008-8933-085 30 40 20 0 10R-2009-9606-019 20 75 0 0 5 R-2009-9606-020 20 80 0 0 0 R-2009-9606-03020 40 40 0 0 R-2009-9606-032 20 0 40 40 0

Release studies were performed in triplicates as follows. The filamentswere cut into one milligram implant (approximately 3-mm long), and wasplaced into a 10-mL vial containing 0.01M phosphate buffered saline (pH7.4). The samples were then transferred into a shaking water bath set at37° C. and 50 rpm. At various time-points, the solution was removed andanalyzed by HPLC for the amount of released latanoprost. The removedsolution is replaced with fresh phosphate buffered saline solution. Drugrelease profiles are shown FIGS. 2A-C.

The present invention is not to be limited in scope by the exemplifiedembodiments, which are only intended as illustrations of specificaspects of the invention.

In general, considering both the solvent cast thin film and the extrudedimplants of this invention, latanoprost may comprise from 10 to 60%,more preferably from 20 to 50%, e.g. 30%, of the implant and the implantfurther comprising a mixture of two or more biodegradable polymers,selected from the group consisting of PLA, PLGA and mixtures thereof.The range of concentrations of the preferred polymer components that canbe used in the implant of the invention are 10 to 60%, R208; 10 to 60%,R203S; 10 to 60%, RG752S, and 10 to 60%, 755S.

Unless otherwise specified the percentages of drug, polymer(s), and PEG(co-solvent) given above represent the mass of the component relative tothe total mass of the composition or implant formulation, the ratiomultiplied by 100 to give the weight/weight percentage of the componentin the implant (i.e, the % w/w).

Various other modifications of the invention, in addition to thosedisclosed herein, will be apparent to those skilled in the art by acareful reading of the specification, including the claims, asoriginally filed. It is intended that all such modifications will fallwithin the scope of the appended claims.

1. A biodegradable intraocular implant for reducing intraocular pressurein an eye of an individual in need thereof, the implant comprisinglatanoprost and one or more biodegradable polymers, wherein: a) theimplant does not contain bimatoprost; b) the implant is in the form of afilm or an extruded filament; c) said filament optionally furthercomprises a polyethylene glycol (PEG); d) said film is about 100 μm toabout 500 μm thick and about 2 to about 6 mm in diameter; e) thesolubility parameters for each of the latanoprost, the biodegradablepolymer(s), and the PEG differ one from the other by no more than 10MPa“²; f) the implant releases latanoprost continuously for at least 30days after placement in the eye of the individual; and wherein g) thebiodegradable polymer(s) is/are selected from the group consisting of i)an ester terminated poly(D,L-lactide) having an inherent viscosity ofabout 1.8-2.2 dl/g (R208); ii) an ester terminated poly(D,L-lactide)having an inherent viscosity of about 0.16-0.24 dl/g (R2025); iii) anacid terminated poly(D,L-lactide) having an inherent viscosity of about0.16-0.24 dl/g (R202H); iv) an ester terminated poly(D,L-lactide) havingan inherent viscosity of about 0.25-0.35 dl/g (R2035); v) an esterterminated poly(D,L-lactide-co-glycolide) having an inherent viscosityof about 0.16-0.24 dl/g and a D,L-lactide to glycolide ratio of about75:25 (RG7525); and vi) an ester terminatedpoly(D,L-lactide-co-glycolide) having an inherent viscosity of about0.50-0.70 dl/g and a D,L-lactide to glycolide ratio of about 75:25(RG755S).
 2. A biodegradable implant according to claim 1, wherein theimplant does not contain a prostamide.
 3. A film according to claim 1,wherein said film is in the form of a rolled film that can partially orcompletely unfurl upon insertion into the eye.
 4. A biodegradableimplant according to claim 1, wherein said extruded filament comprisesabout 5 to about 10% by weight PEG
 3350. 5. A biodegradable implantaccording to claim 1, said implant in the form of a film and comprisingabout 30% by weight latanoprost, about 35% by weight of an esterterminated poly(D,L-lactide) having an inherent viscosity of about1.8-2.2 dl/g (R208), and about 35% by weight of an ester terminatedpoly(D,L-lactide-co-glycolide) having an inherent viscosity of about0.16-0.24 dl/g and a D,L-lactide:glycolide ratio of about 75:25(RG752S).
 6. A biodegradable implant according to claim 1, said implantin the form of a film and comprising about 30% by weight latanoprost,about 20% by weight of an ester terminated poly(D,L-lactide) having aninherent viscosity of about 1.8-2.2 dl/g (R208), and about 50% by weightof an ester terminated poly(D,L-lactide-co-glycolide) having an inherentviscosity of about 0.16-0.24 dl/g and a D,L-lactide:glycolide ratio ofabout 75:25 (RG752S).
 7. A biodegradable implant according to claim 1,said implant in the form of an extruded filament and consisting of about20% by weight latanoprost, about 40% by weight of an ester terminatedpoly(D,L-lactide-co-glycolide) having an inherent viscosity of about0.16-0.24 dl/g and a D,L-lactide:glycolide ratio of about 75:25(RG752S); and about 40% by weight of an ester terminatedpoly(D,L-lactide) having an inherent viscosity of about 0.16-0.24 dl/g(R202S).
 8. A biodegradable implant according to claim 1, said implantin the form of an extruded filament and consisting of about 20% byweight latanoprost, about 40% by weight of an ester terminatedpoly(D,L-lactide) having an inherent viscosity of about 0.16-0.24 dl/g(RG202S), and about 40% by weight of an acid terminatedpoly(D,L-lactide) having an inherent viscosity of about 0.16-0.24 dl/g(R202H).
 9. A method for making a biodegradable intraocular implantaccording to claim 1, the method comprising: a) dissolving thebiodegradable polymer(s) in an organic solvent under constant stirringto form a first solution; b) adding latanoprost to the first solutionunder constant stirring to form a second solution; c) sonicating thesecond solution to remove air bubbles; d) casting the second solutioninto a glass dish; e) evaporating the solvent to form a dry film; and f)cutting the film into circular portions of about 2 to about 6 mm indiameter each.
 10. The method of claim 9, wherein the solvent isdichloromethane.
 11. The method of claim 9, further comprising rollingsaid circular portions to form a rolled film implant that can partiallyor completely unfurl upon placement in the eye of an individualsuffering from elevated intraocular pressure.
 12. A method for making abiodegradable intraocular implant according to claim 1, the methodcomprising: a) mixing the latanoprost, the biodegradable polymer(s), andoptionally the PEG to form a mixture; and b) extruding the mixture at atemperature of less than about 80° C. to form a filament that willrelease latanoprost continuously for at least 30 days after placement inthe eye of the individual.
 13. A method for providing an ocular implantto a patient in need thereof, wherein the implant is in the form of afilm rolled into a cylindrical shape, the rolled film comprisinglatanoprost and a biodegradable polymer, the method comprising placingthe rolled film in the eye of the patient, whereby said film can unrollor partially unroll to provide a large surface for drug diffusion, andwherein the implant releases latanoprost continuously for at least 30days after placement in the eye of the patient.
 14. The method of claim12, wherein the unrolled film is circular, about 100 μm to about 500 μmthick, and about 2 mm to about 6 mm in diameter.
 15. The method of claim12, wherein the patient in need is suffering from elevated intraocularpressure.